The involvement of the dysfunction of transcrption factor in the pathogenesis of stress-related psychiatric disorders

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To elucidate the pathogenesis of stress-related psychiatric disorders (SRPDs), I examined whether stress and/or antidepressant drug treatments could regulate the phosphorylation of cAMP response element binding protein (CREB) and calcineurin (CaN) activity in rat frontal cortex and hippocampus.A marked induction of phospho CREB (p-CREB) followed by the transient significant downregulation was found in response to acute restraint stress (ARS). Whereas acute antidepressant treatments significantly induced the levels of p-CREB, chronic as well as chronic plus acute antidepressant treatments had no change in p-CREB expression. Chronic pretreatment with antidepressant downregulated the induction of p-CREB in response to ARS.Neither ARS nor antidepressant treatments had a significant change in the levels of CaN mRNA. In contrast, while ARS significantly induced the serine/threonine phosphatase activity of CaN, both acute and chronic administration of antidepressants significantly upregulated CaN activity.To examine whether the imbalance of CREB phosphorylation was involved in the stress vulnerability, the influence of single prolonged stress (SPS) followed by ARS on p-CREB expression and CaN activity. Both p-CREB expression and CaN activity by SPS followed by ARS were higher than those by ARS, but the differences did not reach the significance.Based on these findings, it is suggested that the changes in gene expression mediated by CREB phosphorylation could play an important role in the pathogenesis of SRPDs, and the marked induction of p-CREB and CaN activity in response to stress may be involved in the acquisition of stress vulnerability.